Dr Marija Fjodorova

(she/her)

BA (Hons), PhD, FHEA

Publication

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Research

My research focuses on the development and function of neuronal populations in the basal ganglia, with emphasis on how psychiatric and neurodegenerative disorders affect synaptic signalling and downstream molecular mechanisms in striatal neurons. The focus of my work is on the development and synaptic function of striatal medium spiny, midbrain dopamine and cortical neurons and subsequent cortico-striatal and midbrain-striatal network formation. The aim is to unravel underlying molecular events in healthy and diseased neurons via an integrated experimental approach involving in vitro human stem cell differentiation, contemporary genetic manipulation, and transcriptomic analysis. My goal is to understand molecular mechanisms of basal ganglia function and communication in health and neurological disorders and translate these findings into innovative therapeutic interventions. 

Striatal Neuron Differentiation

Early in my postdoctoral career, I developed an interest in using human pluripotent stem cells to generate clinically relevant neurons expanding my work into stem cell neurobiology and in vitro disease modelling in Professor Meng Li’s group at the Neuroscience and Mental Health Innovation Institute (Cardiff University). My research on induction of striatal neurons from stem cells identified a role, first for Activin A and then alantolactone, within the transforming growth factor beta (TGFβ) signalling pathway in medium spiny neuron differentiation. This TGFβ signalling-based protocol is recognised in the field as one of the main approaches to derive medium spiny neurons in vitro.

A Role for BCL11B in Medium Spiny Neuron Homeostasis

In parallel to the above work, I led the study to investigate how BCL11B (aka CTIP2) transcription factor deficiency drives striatal and cortical neuron degeneration and dysfunction. Using CRISPR technology, I have genetically modified human embryonic stem cell lines lacking this transcription factor and in turn characterised BCL11B-null neurons via an integrated approach involving in vitro differentiation, bulk RNAseq analysis, biochemical and neuronal activity assays. This research identified a striatal-specific role for BCL11B in protein kinase A-dependent protein phosphorylation and calcium signalling in response to dopamine and glutamate stimulation in medium spiny neurons with implications for schizophrenia and Huntington’s disease. My collaborations with scientists in the Huntington’s disease field in the Brain Repair Group (Cardiff University) and Inserm (Paris) have further confirmed this hypothesis and demonstrated similar deficits in striatal neurons in rodent and human pluripotent stem cell models of Huntington’s disease.

Medium Spiny Neurons in Neurodevelopmental Disorders

Recently, I have extended my study of striatal neurons and their contribution to the pathogenesis of neurodevelopmental disorders, with pilot work focused on cell lines carrying either duplication or deletion of the 16p11.2 locus, a copy number variation that confers substantial risk for schizophrenia and autism spectrum disorders. This initial work provides strong evidence of deficits in medium spiny neuron differentiation from human induced pluripotent stem cells harbouring the 16p11.2 copy number variations supporting the hypothesis that disruption to the development and function of striatal neurons are central to these disorders, with a role that is distinct from cortical excitatory and inhibitory neurons.

Teaching

I am available to supervise undergraduate and postgraduate students.

Biography

2024: Hodge Lecturer in Cellular Psychiatry, School of Medicine, Cardiff University

My research vision is to understand the biological basis of mental health and neurodevelopmental disorders (NDDs), with the goal of enhancing early diagnosis and treatment. I aim to elucidate how genetic mutations increasing risk for NDDs disrupt human neuron development and function within basal ganglia circuits. My goal is to determine the extent of these contributions to disease pathogenesis and pave ways for future drug discovery.

2021 - 2023: Research Associate, School of Medicine, Cardiff University

Medical Research Council UK funded project titled “Targeting ERK signalling to ameliorate intellectual disability and autism spectrum disorder associated with chromosomal rearrangements at 16p11.2” in Professors Meng Li’s and Riccardo Brambilla’s groups.
Project outcomes:
I. Have studied striatal medium spiny neuron and cortical neuron development and function in patient-derived induced pluripotent stem cells carrying neurodevelopmental disorder-associated deletions and duplications of the 16p11.2 region. Have identified profound deficits in striatal neurogenesis and medium spiny neuron subtype imbalance in both 16p11.2 genotypes using single-cell RNA sequencing and stem cell differentiation approaches.
II. Have developed in vitro co-culture models of ‘basal ganglia’-like circuits with the aim to assess deficits in network establishment and signalling between cortico-striatal/midbrain-striatal synaptic partners in disease models.

2018 - 2021: Research Associate, School of Medicine, Cardiff University

Medical Research Council UK funded project titled “How CTIP2 deficiency drives medium spiny neuron degeneration and dysfunction” in Prof Meng Li’s Stem Cell Neurogenesis group.
Project outcomes: Discovered a role for BCL11B (aka CTIP2) in protein phosphorylation and calcium signalling in striatal medium spiny neurons with implications for schizophrenia and Huntington’s disease.

2013 - 2018: Research Associate, School of Biosciences, Cardiff University

EU 7th Framework Programme Repair-HD project in Prof Meng Li’s Stem Cell Neurogenesis group.
The main focus of this work was on the developmental biology of human neurons, specifically medium spiny neurons and dopamine neurons. The aim was to unravel molecular mechanisms behind neural fate induction and subsequent terminal differentiation via an integrated experimental approach involving in vitro stem cell differentiation and contemporary genetic manipulation. Novel strategies that drive pluripotent stem cells into clinically relevant neurons were devised and evaluated for their efficacy and functionality in vivo.
Project outcomes:
I. Generated knock-out and over-expressing human embryonic stem cell lines to study a role for BCL11B transcription factor in the development and functional maturation of striatal neurons. Revealed that BCL11B-deficient medium spiny neurons exhibit Huntington’s disease-like neuronal defects.
II. Optimised differentiation protocols for human embryonic stem cells and produced transplantable and functioning medium spiny and dopamine neurons that were successfully tested in vivo in collaboration with the Brain Repair Group at Cardiff University and Inserm in Paris.

2009 - 2013: PhD, Cardiff University

Wellcome Trust PhD in Integrative Neuroscience under the supervision of Professor Stephen Dunnett titled " Characterisation of embryonic ventral mesencephalon grafts in a rat model of Parkinson's disease". I studied striatal circuitry repair in a rat model of Parkinson’s disease and demonstrated how embryonic donor age and transplantation site affect survival and distribution of dopaminergic neurons in the grafts. This research has provided a platform for improvements to cell replacement therapy in Parkinson’s disease.

2006 - 2009: BEng (Hons) Medical Engineering (1st Class), University of Bradford

Honours and awards

2024: Fellowship of the Higher Education Academy (FHEA)